Coordinating biological rhythms (chronobiology) with medical treatment is called chronotherapy. Chronotherapy takes into consideration a person's biological rhythms in determining the timing—and sometimes the amount—of medication to optimize desired effects of a drug(s) and minimize the undesired effects. The synchronization of medication levels to the biological rhythms of disease activity is playing an increasing role in the management of common cardiovascular conditions such as hypertension, elevated cholesterol, angina, stroke and ischemic heart disease, according to experts in this new and ever-expanding field. For example, in humans, at 1 am post-surgical death is most likely; at 2 am peptic ulcers flare up; at 3 am blood pressure bottoms out; at 4 am asthma is at its worst. When one wakes up, hay fever is at its most tormenting, and in the morning hours, as ones blood pressure rises to meet the day, one is most likely to suffer a heart attack or stroke. Rheumatoid arthritis improves through the day, but osteoarthritis grows worse. Alcohol is least toxic to the body at around 5 pm: cocktail hour.
The first application of chronotherapy, in the 1960s, was a synthetic corticosterdid tablet (Medrol, Upjohn). Clinicians found that when used in the morning, the drug was more effective and caused fewer adverse reactions. Another example of a commercial product employing chronotherapy is the bronchodilator, Uniphyl®, a long-acting theophylline preparation manufactured by Purdue Frederick (approved by the FDA in 1989). Taken once a day at dinner to control night-time asthma symptoms. Uniphyl causes theophylline blood levels to reach their peak and improve lung function during the difficult morning hours.
Oral controlled release delivery systems may also be capable of passing over the entire tract of the small intestine, including the duodenum, jejunum, and ileum, so that the active ingredients can be released directly in the colon, if such site specific delivery is desired. One means of accomplishing this is by providing a coating surrounding the active pharmaceutical formulation core so as to preserve the integrity of the formulation while it is passing through the gastric tract. The high acidity of the gastric tract and presence of proteolytic and other enzymes therein generates a highly digestive environment that readily disintegrates pharmaceutical formulations that do not possess some type of gastro-resistance protection. This disintegration would typically have a detrimental effect upon the sustained release of the active agent. Such coated pharmaceutical formulations, in addition to slowing the release rate of the active agent contained within the core of the tablet, can also effectuate a delay in the release of the active ingredient for a desired period of time such that the dissolution of the active drug core can be delayed. Examples of coated pharmaceutical delivery systems for delayed release can be found in U.S. Pat. No. 4,863,742 (Panoz et al.) and U.S. Pat. No. 5,891,474 (Busetti et al.), as well as in European Patent Applications Nos. 366 621, 572 942 and 629 398. In the delayed release tablets described in each of these references, the therapeutically active drug core is coated with at least one and potentially several layers of coating, wherein the layers of coating have a direct effect upon the timed release of the active drug within the tablet core into the system of the patient.
PCT publications WO 02/072033 and WO 02/072034, the disclosures of which are hereby incorporated by reference, disclose chronotherapeutic pharmaceutical formulations comprising a core containing an active agent (e.g., a drug) and a delayed release compression coating comprising a natural or synthetic gum applied onto the surface of the core.
It is considered desirable by those skilled in the art to provide an oral controlled release delivery system that is adaptable to deliver a drug(s) such that release rates and drug plasma profiles can be matched to physiological and chronotherapeutic requirements.